Denny C T, Shah N P, Ogden S, Willman C, McConnell T, Crist W, Carroll A, Witte O N
Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, University of California, School of Medicine, Los Angeles 90024.
Proc Natl Acad Sci U S A. 1989 Jun;86(11):4254-8. doi: 10.1073/pnas.86.11.4254.
The Philadelphia chromosome associated with acute lymphoblastic leukemia (ALL) has been linked to a hybrid BCR/ABL protein product that differs from that found in chronic myelogenous leukemia. This implies that the molecular structures of the two chromosomal translocations also differ. Localization of translocation breakpoints in Philadelphia chromosome-positive ALL has been impeded due to the only partial characterization of the BCR locus. We have isolated the entire 130-kilobase BCR genomic locus from a human cosmid library. A series of five single-copy genomic probes from the 70-kilobase first intron of BCR were used to localize rearrangements in 8 of 10 Philadelphia chromosome-positive ALLs. We have demonstrated that these breakpoints are all located at the 3' end of the intron around an unusual restriction fragment length polymorphism caused by deletion of a 1-kilobase fragment containing Alu family reiterated sequences. This clustering is unexpected in light of previous theories of rearrangement in Philadelphia chromosome-positive chronic myelogenous leukemia that would have predicted a random dispersion of breakpoints in the first intron in Philadelphia chromosome-positive ALL. The proximity of the translocation breakpoints to this constitutive deletion may indicate shared mechanisms of rearrangement or that such polymorphisms mark areas of the genome prone to recombination.
与急性淋巴细胞白血病（ALL）相关的费城染色体与一种混合的BCR/ABL蛋白产物有关，该产物与慢性粒细胞白血病中发现的不同。这意味着两种染色体易位的分子结构也不同。由于BCR基因座仅得到部分表征，费城染色体阳性ALL中易位断点的定位受到了阻碍。我们从一个人类黏粒文库中分离出了完整的130千碱基的BCR基因组基因座。使用了一系列来自BCR基因70千碱基第一内含子的五个单拷贝基因组探针来定位10例费城染色体阳性ALL中8例的重排情况。我们已经证明，这些断点都位于内含子的3'端，围绕着一个由缺失一个包含Alu家族重复序列的1千碱基片段引起的不寻常的限制性片段长度多态性。鉴于之前关于费城染色体阳性慢性粒细胞白血病重排的理论预测费城染色体阳性ALL中第一内含子的断点会随机分散，这种聚类是出乎意料的。易位断点与这种组成性缺失的接近可能表明存在共同的重排机制，或者这种多态性标记了基因组中易于重组的区域。
